The central aim of the proposed research program is to evaluate a set of specific hypotheses about the basis for nonverbal cognitive impairments in children with chromosome 22q11.2 deletion syndrome (22q). The proposed series of studies builds directly upon the exploratory analyses tested in the first period of funding (4/1/03 - 3/31/08). Specifically, we propose that this genetic syndrome leads to early developmental changes in the structure and function of clearly delineated neural circuits for basic spatiotemporal cognition. During childhood, this dysfunction cascades into impairments in basic magnitude and then numerical processes, because of the central role that representations of space and time play in their construction. We propose that this is due to spatiotemporal hypergranularity; the increase in grain size and thus reduced resolution of mental representations of spatial and temporal information. By raising detection thresholds and introducing error into all spatiotemporal processing, this representational degradation defines the hypothesized alterations in these basic processes [that] will generate explanations of [...] impairments in the domains of visuospatial and numerical cognition (p.1 previous application). The result is that spatiotemporal processes develop atypically and thereby produce the characteristic impairments in nonverbal cognitive domains that are a hallmark feature of 22q. The chromosome 22q11.2 deletion syndrome (encompassing DiGeorge, Shprintzen and Velocardiofacial Syndromes) is quite prevalent (~1:4000 live births) yet little is known about its neurocognitive implications. Two Specific Aims are designed to 1) Identify dysfunctions in the interaction of spatial and temporal processing and measure the resolution of spatiotemporal attentional selection, and 2) Identify neural substrates of spatiotemporal dysfunction and of hypergranularity. The former will employ a battery of cognitive and psychophysical experiments to define and measure spatiotemporal cognitive impairments in children with 22q. The latter will examine a specific neural circuitry hypothesis using structural, connectivity and functional measures. Specificity will be addressed by comparing results from children with 22q to typically developing controls and those with sex chromosome aneuploidies, another developmental disability group with stronger spatial than verbal abilities. We expect results to create a neurocognitive explanation of spatiotemporal and numerical impairments in 22q specific enough to be directly translated into therapeutic interventions in the next funding period. PUBLIC HEALTH RELEVANCE: This project tests a very specific account of changes in the minds and brains of children with a common but ill-understood genetic disorder called chromosome 22q11.2 deletion. This account might explain the learning difficulties that they experience. If this explanation is supported by the research, problems in thinking and reasoning about measurements of space, time and numbers could be reduced or remedied by using the results to design computer based interventions that could benefits many tens of thousands of children.